Subtle alterations in the function of receptors within the central nervous system (CNS) are thought to play a role in the pathogenesis of various neuropsychiatric disorders. Moreover, the efficacy of several antipsychotic and antidepressant drugs has been attributed to their ability to induce adaptive changes in receptormediated functions. Long term exposure of laboratory animals to these drugs results in either increased or decreased sensitivity of certain membrane-bound receptors. Our studies have demonstrated that such treatments induce long lasting alterations in the phosphorylation of specific proteins located in these membranes. The present proposal will study the role of specific phosphoproteins in mechanisms underlying the regulation and adaptation of catecholamine receptors in the CNS. Receptor adaptation in dopaminergic and adrenergic synapses will be induced by subjecting rats to short- and long-term treatments with psychotropic drugs. Molecular manifestations of the development of receptor sub- or supersensitivity will be determined by simultaneous analyses of agonist-binding, adenylate cyclase and endogenous phosphorylative activities in appropriate subcellular fractions of select brain regions from placebo- and drug-treated rats. The focus of investigation will be on the interactions between these three variables of receptor function. Model systems, i.e. brain slices and neuroblastoma cells in culture are expected to permit a more refined characterization of such interactions. Preliminary studies in our laboratory have indicated that the binding of agonists to their recognition sites, as well as the activity of receptor-coupled adenylate cyclase are affected by agonist-induced alterations in the phosphorylation of specific proteins. We shall carry out a systematic series of experiments designed to reveal cause-effect relationships between drug and agonist-induced changes in phosphorylation on the one hand, and the activity of recognition sites (specific-binding) and effector sites (transmitter-sensitive adenylate cyclase) of receptors on the other. These studies may contribute to the development of novel approaches in the treatment of mental illnesses associated with receptor dysfunction.